Cells in the blood vessel are constantly subjected to hemodynamic forces resulting from pulsatile blood pressure and flow. These forces regulate a variety of functions in both endothelial cells and vascular SMCs including migration, proliferation and apoptosis. Studies on Rho family small GTPases have shown that Rho, Rac, and Cdc42 are involved in the intracellular signaling pathways elicited by both mechanical forces and biochemical stimuli, leading to changes in cell structure and function. Although mechanical and biochemical stimuli act on the same small GTPase pathways, the interplay between these two types of stimuli in vascular SMCs is not clearly understood. My hypothesis is that mechanical forces, as well as biochemical stimuli, cause activation and a later desensitization of cellular signaling pathways that would reduce the responsiveness of vascular SMC to the other type of stimulus. This proposal has three specific aims. Specific Aim 1 is to define the effect of PDGF on cyclic strain stimulation of small GTPases. Specific Aim 2 is to define the effect of cyclic strain on PDGF stimulation of small GTPases. Specific Aim 3 is to elucidate the molecular mechanisms that regulate the response of small GTPases to the combination of cyclic strain and PDGF stimulation. The results of this interdisciplinary study will help to better understand the fundamental molecular processes involved in the pathogenesis of vascular disorders such as hypertension.